The active thyroid hormones are designated T-4 and T-3. In the blood, T-4 and T-3 are almost entirely bound to plasma proteins. Thyroxine binding globulin (TBG) is normally the major determinant of overall binding intensity of T-4. The interaction between T-4 and its binding proteins is in reversible binding equilibrium. Only a small portion, usually about 0.03 percent of T-4 is free in blood. However, T-3 is not as readily bound, and as a consequence, the normal proportion of free T-3 is eight to ten times greater than that of T-4. Only free (unbound) hormone is available to tissues. Therefore, the metabolic state of the patient correlates more closely with the concentration of free hormone, rather than the total concentration of hormone, in plasma.
There are two general types of disturbances of the thyroid hormone-plasma protein interaction. In the first type of disturbance, an increased amount of TBG or other serum binding proteins or the appearance of abnormal serum binding proteins results in a lowered free hormone level. Total hormone concentration in serum may then increase until the concentration of free hormone is restored to normal. In the second type of disturbance, the concentration of thyroxine-binding globulin (TBG) is normal, but the amount of thyroid hormone is abnormal. In this type of disorder, the proportion of free hormone changes in the same direction as the change in hormone supply.
When the amount of free T-4 is too low, patients can be treated with synthetic T-4 (levothyroxine). In that case it is important to determine how much administered synthetic T-4 will be bound by TBG, rather than the total thyroxine concentration after administration of T-4, since only unbound hormone is effective in treating the patient.
A number of assays related to hormone concentration and binding in blood have been developed. Free T-4 concentration can be measured by equilibrium dialysis of serum enriched with a small amount of labeled T-4. The percent of T-4 that is dialyzable, and therefore free, is determined. From that number, the percentage that is bound can be calculated. However, the dialysis technique is cumbersome and has not generally been useful for clinical purposes. An in vitro uptake test in which serum is incubated with labeled T-4 or T-3 and then with an insoluble particulate matter such as resin or charcoal that non-specifically binds free hormone has also been developed. The percentage of labeled hormone associated with the particulate matter varies inversely with the concentration of unoccupied sites among serum proteins and their affinity for the labeled hormone.
Methods which would more accurately determine uptake values of TBG would assist the clinician in differentiating low T-4 state of a non-thyroidal illness from overt thyroxine deficiency of hypothyroidism. Such methods would also allow the clinician to more accurately determine the amount of synthetic T-4 to administer to alleviate symptoms produced by hypothyroid disease.